Alkyl-xanthin and process of making same.



UNITED STATES PATENT OFFICE.

FRITZ AOH, OF MANNHEIM, GERMANY, ASSIGNOB TO 0. F. BOEHRINGER dc SOEHNE, OF WALDHOF, GERMANY.

ALKYL-XANTHIN AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 631,759, dated August 22, 1899.

Application filed February 18,1 89 8 To ctZZ whom it may concern:

Be it known that I, FRITZ AOH, a citizen of the Empire of Germany, residing at Mannheim, in the Empire of Germany, have invented certain new and useful Improvements in Alkyl-Xanthins andMethods of Preparing the Same; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

This invention relates to the manufacture of xanthins and their derivatives, and more particularly to the preparation of this class of bodies from alkylized uric acids.

In order to define more exactly the ground which this invention occupies in the art, it is to be stated that a method has heretofore been found of obtaining the halogen derivatives of alkylized xanthins by the action of phosphorus chlorid thereon, the xanthins themselves being then obtained by reducing the halogen derivatives. This method has been set forth in United States patents to Emil Fischer, Nos. 569,489 and 569,l90, dated October 13, 1896. According to these patents such conversion was, however, only possible for such alkyl-uric acids as contained two alkyl groups in the alloxan ring, and whose structure would be represented by the general formula- 0 tion 1 and position 3 could, according to that Serial No, 670,849- (Specimens) method, be converted into Xanthins. To proceed from mono-methyl-uric acids or from other dimethyl-uric acids to halogen or chloro-Xanthins has hitherto been impossible. My investigations and experiments in this field have resulted in the discovery that all uric acids which have not been completely alkylized may be converted into the corresponding chloro-Xanthins, provided no alkyl group has been bound to the nitrogen atom in the position 9.- In the latter case only chloro-purins would result. This discovery demonstrates that, contrary to the opinion hitherto entertained, it is immaterial for the preparation of xanthins from uric acids whether the nitrogen atoms 1 and 3.-7:. 6., those in the alloxan ringare alkylized or not. All that is material in this respect is that the nitrogen atom 9 be not alkylized. I

have, moreover, ascertained as a result of my investigations that it is necessary to act upon the alkylized uric acid with phosphorous-oxychlorid alone in order to proceed to Xanthins and that this result cannot be attainedif the phosphorous-oxy-chlorid acts on the alkyluric acid in conjunction with phosphoruspenta-chlorid, for example. A comparison of the entirely and essentially different results obtained by acting on the same alkyluric acid first with phosphorus-oxy-chlorid together with phosphorus-penta-chlorid, according to the methods heretofore known, and then with phosphorus-oxy-chlorid alone will serve admirably to emphasize the essence of the present invention. Thus if, for example, 8 5 7-monomethyl-uric acid is submitted to the joint action of phosphorus-oxy-chlorid and phosphorus-penta-chlorid the oxygen, bound to the alloxan ring, alone is replaced by chlorin, the resultant compound being 7 -methylo 8-0xy-2-6-dichloropurin:

HN-OO N:C.Ol

oo CN.CH3-- OI.O o N.cI-L

l l ii i If, however, phosphorus-oxy-chlorid alone is caused to react on 7-monomethyl-uric acid, chlorin is substituted for the oxygen occupying the position-8, whereby the xanthin derivative, 7-m ethyl 2-6-clioxy- 8- chloropurin or 7-methyl-chlor0-Xanthin, is obtained:

I-IN-CO HN-OO Again, if 3-7-dimethyl-uric acid be treated with phosphorus-oXy-chlorid, together with posphorus-penta-chlorid, there is formed 3-7- dimethyl-2-S-dioxy-(i-chloropurin, as shown in Berichie (Zer- Deutschen C'he m ischen Gcsellschaft, Vol. 28, page 2486, and Vol. 30, page 554:

IIN-OO N:O.Cl

If, on the other hand, the phosphorus-oxychlorid alone is caused to act upon the 3-7- dimethyl-uric acid,substitution of chlorin will again take place in the position 8 instead of in the alloxan ring, the chloro xauthin 3-7- dimethyl-2-6-dioxy- -chloropurin or chloro- I have found that the same result is obtained with other alkyl-uric acids, and in general my I invention shows that the use of phosphorusoXy-chlorid alone results in. the production of chloro-Xanthins when acting upon alkyl-uric acids which have no alkyl group bound to the N occupying the position 9, while the treatment of such uric acids with both phosphoruspenta-chlorid and the oXy-chlorid would result in chloropurins, which are not Xanthin derivatives. I

According to my observations intermediate products apparently containing phosphorus and chlorin are at first formed when phosphorus-oxy-chlorid reacts upon alkylized'uric acids, these intermediate bodies being subsequently changed into chloro-xanthius by treat ment with suitable means, such as alcohol or Water, While phosphorus acid and hydrochloric acid are split off.

The chloro-Xanthins obtained under my invention are converted into higher alkylized products by employing the alkylizing methods which are in use in connection with the uric acid and xanthin series. Thus, for example, chloro-theobromin may be obtained from 3-methyl chloro-xanthiu on further methylation, the chloro-theobromin being in turn readily susceptible of conversion into chloro-caffein by the same methods.

The chloro-xanthins are converted into the corresponding xanthins by reducing methods.

It is to be noted that under my invention other alkyl radicals thanthe methyl group may be introduced into the xanthin molecule. Thus the 3-methyl-chloro-xanthin is readily converted into 3-methyl-1-7-diethyl-chloroxanthin by introducing the ethyl radical into the former.

For the purposes of my invention it is unimportant Whether the lower chloro xanthins are first alkylized and then reduced, or vice versa. In both ways I may proceed to the higher alkylized xanthins such as caffein.

The method above set forth of submitting alkylized uric acids generally which have no alkyl in the position 9 to the action of phosphorus-oxy-chlorid alone and subsequently reducing and alkylizing such products has been broadly covered in my application Serial No. 670,847, filed concurrently herewith, said application also claiming specifically the application of such methods to 3-alkyl-uric acids. Hence this application does not broadly claim such method; but my present invention consists in the specific application of these methods to 3-7-dialkyl-nric acids that is to say, the treatment of the same with phosphorus-oXy-chlorid alone and in the subsequent reduction and alkylization methods applied to the resultant eompound,which also forms a part of my present invention.

My present invention, moreover, consists in such additional features and methods as will be fully explained hereinafter and pointed out in the claims.

In order to fully disclose my invention, I will now describe the same in detail, first reciting the method of preparing the chlorotheobromin or chloro-dimethyl-Xanthin from 3-7-dimethyl-uric acid and then in further examples setting forth the method of converting said new compound into chloro-caffein and into theobromin.

'1. Preparation of3-7-cltmethyZ-Q-6-(Hoary-8- chloro-puri-n or chloro-t7reobromin from 3-7- 1 dimeih-yZ-wric acid.0ne part, by weight, of

3-7-dimethyl-uric acid which has been reduced to the finest possible powder is added to five parts, by volume, of phosphorus-oxychlorid and the whole boiled with reflux until a clear solution is formed. This requires about twenty hours. From the resulting liquid, which is slightly colored, the unchanged phosphorus-oxy-chlorid is distilled off in vacuo and the'residue is dissolved with alcohol. The solution is then boiled. After a short time the chloro-theobromin which has been formed begins to crystallize out of the solution. The reaction takes place about according to the equation:

HN-OO 3 oo C-NCI I +Poc1,,:

OO OII .NONI-I I-IN-CO 3 0C O-NCH -ll PO (L.Ol CH .NON

The crystals are then drained by filtration and dissolved in dilute alkali and treated with carbon for decoloration,whereupon the chlorotheobromin is thrown out by dilute sulfuric acid. The colorless product so obtained has the composition indicated by the formula O H Np Ol and the structure- HN- CO Wherefore I term it 3-7-dimethyl-2-6-d-ioxy- S-chloropurin or 3-7-dimethyl-8-chloro-Xanthin or 8 chloro theobrornin. The above structure is established by the ready and smooth conversion of this new compound into chloro-caffein, as will be set forth under head 2.

Chloro-theobromin heated with chlorinewater or with dilute nitric acid gives the murexide test. On heating the same rapidly it melts at about 292 to 293 centigrade to a slightly-coloredliquid, which soon congeals to a crystalline mass on cooling. It dissolves in about two hundred and fifty parts of water on boiling. From such aqueous solution it is thrown out in the form of colorless, vitreous, shining, short prisms on cooling slowly and in the form of fine needles aggregated in bunches on cooling rapidly. It is only difficultly soluble in boiling alcohol. 011 the other hand, it is readily soluble in dilute alkalies and dilute Warm ammonia. From asolution of the same in soda-lye its sodium salt is rapidly thrown out in the form of fine acicular crys tals by concentrated soda-lye. If an ammoniacal solution of the same be added to an am moniacal silver solution and the ammonia be removed by boiling, a gelatinous colorless silver salt of the chloro-theobromin is thrown out.

52. Preparation ofchloro-caficinfrom chlorothe0br0min.-I find that alkylizing methods may be employed with chloro-theobromin and that when methylating agents are applied to chloro-theobromin, which is 3-7-dimethyl-2- 6-dioxy-S-chloro-purin or 3-7-dimethyl-8-chloro-xanthin, trimethyl-chloro-xanthin or chloro-cafEein will be obtained. If two parts, by weight, of the chloro-theobromin be dissolved in seven volumes of double-normal potash-lye (potassium hydrate) and seven volumes of Water and heated centigrade under pressure, together with one and one-half parts of methyl-iodid, this temperature being maintained for three hours and the liquid constantly agitated, the formation of chloro-caf fein will take place. The greater portion of the same is thrown out in the form of fine acicnlar crystals after cooling, while the remainder is obtained by extraction with a suitable vehicle, such as chloroform. The following equation explains the reaction which takes place:

HN-CO ou,.N-o-N emu-co The theoretical and practical yield are identical.

Preparation of 3- 7 -dimet7tyZ-Q 6-(Zt00cypart'n or theobromi'n from chloro -ihe0bromin.-lf one part, by weight, of chloro-theobromin or 3-7-dimethyl 2 6 dioXy-S-chloropurin, which'has been described hereinabove, be heated on the water-bath with eight times its weight of fuming hydriodic acid of the specific gravity 1.96, about one-half part of phosphonium-iodid being added, a colorless clear solution will be obtained after the lapse of from fifteen to twenty minutes. This indicates that the reduction of the chloro-theobromin has been completed. The liquid is? then evaporated to complete dryness to eliminate the surplus of hydriodic acid. The colorless crystalline residue is then taken up with water, whereby the said residue is first dissolved. After a short time, however, the formation of colorless indistinct crystals ensues. lized from boiling water, and they possess all of the characteristic properties of theobromin. They crystallize in small colorless prisms, melt at about 345 centigrade without decomposition, and when dissolved in nitric acid they unite with nitrate of silver to form the double salt which forms fine needles. The reducing reaction'whereby the theobro- 'IOO These are redissolved and recrystalmin is formed from the chloro-theobromin is elucidated in the equation:

HN-CO The theoretical and practical yield of the obromin are identical.

The chloro-caffein which may be obtained under my present invention may be further converted into caffein by adopting Well-known methods, and caffein may be obtained also by methylation of the theobromin obtained by reduction of the chloro-theobromin. Thus it will be seen that the new compound, 3-7-dimethyl-S-chloro-Xanthin or chloro-theobromin, is capable of conversion into a higher methylized Xanthin either by first alkylizing and then reducing, or vice versa.

What I claim, and desire to secure by Letters Patent of the United States, is-

1. In the art of preparing xanthins,the process which consists of treating 3-7-dialkyl-uric acid with phosphorus-oxy-chlorid alone.

2. Intheartofpreparingxanthins,theprocess which consists in heating 3-7-dimethyluric acid with phosphorirs-oxy-chlorid alone.

3. In the art of preparing Xanthins,theprocess which consists in boiling 3-7-dimethyluric acid with phosphorus-oxy-chlorid with reflux, the proportions and conditions being substantially as set forth, then distilling off the excess of phosphorus-oxy-chlorid and dissolving the residue with alcohol and boiling such solution.

4. In the art of preparing Xanthins,the process which consists in boiling 3-7-(limethyluric acid with phosphorus-oxy-chlorid with reflux, the proportions and conditions being substantially as set forth, then distilling off the excess oi phosphorus-oXy-chlorid and dissolving the residue with alcohol and boiling such solution, then draining the crystals and dissolving in dilute alkali, and finally precipitating the chloro-theobromin with acid.

5. Asa newchemicalcompound,chloro-theobromin, having the formula above given, which is soluble in much boiling water and soluble with difficulty in boiling alcohol, but readily soluble in dilute alkalies including ammonia, whichcrystallizes in vitreous, shim ing, short prisms out of an aqueous solution on cooling slowly and in the form of fine nee dles aggregated in bunches on rapid cooling, and which melts at about 292 to 293, centigrade.

6. The process which consists in treating chloro-theobromin with an alkylizing agent.

7. The process which consists in dissolving chloro-theobromin in alkali solution and adding thereto an alk-yl-halogen compound and heating the mixture.

8. The process which consists in dissolving chloro-theobromin in caustic-potash lye and water, and adding thereto methyl-iodid, and heating the mixture under pressure while agitating the mixture all substantially in the proportions and under the conditions specified.

9. The process which consists in submitting chloro-theobromin to alkylization and reduction.

10. The process which consists in treating 3-7-dialkyl-uric acid' with phosphorus-oxychlorid alone,then isolating the resultant Xanthin derivative and then submitting the same to alkylization and reduction.

11. The process which consists in treating 3-7-dimethyl-uric acid with phosphorus-oxychlorid, then isolating the resultant chlorotheobromin and inethylating the same, and finally reducing the methylized product.

In testimony whereof I affix my signature in presence of two witnesses.

' FRITZ ACII.

WVitnesses:

LORENZ AcH, J ACOB ADRIAN. 

